Treatment of stereotypic, self-injurious and compulsive behaviors in man and animals using antagonists of NMDA receptors

ABSTRACT

NMDA receptor antagonists can be used in methods of treatment, for reducing the frequency of stereotypic behaviors in animals and for reducing the frequency of analogous compulsive behaviors in humans, for example, those that have been said to be a manifestation of, or related to, obsessive-compulsive disorder. Of particular interest are the (+) enantiomers of opioid receptor binding compounds, which can reduce the frequency of the behaviors, while having no effects from binding at the opioid receptor.

RELATED APPLICATION

[0001] This application is a divisional of co-pending U.S. applicationSer. No. 09/777,316, filed Feb. 5, 2001, which is a divisional ofco-pending U.S. application Ser. No. 09/262,546, filed Mar. 4, 1999,which claims the benefit of U.S. Provisional Application No. 60/077,312,filed Mar. 9, 1998. The entire teachings of the above applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Stereotypic behavior in animals (also called “repetitive” or“compulsive” behavior) has been defined by some researchers as acts thatare repetitive and constant, which may appear to serve no obviouspurpose, and may even be injurious. One of the most common of thesebehaviors is, for example, crib-biting by horses—grabbing and biting ofthe feed bin or of parts of the structure in which the horse is housed(also called “cribbing”—see U.S. Pat. No. 4,692,451 for a description ofthis behavior, associated behaviors, and resulting problems). Anothercommon behavior in dogs is compulsive licking of itself—even to thepoint of aggravating a sore (“lick granuloma” or “acral lick”).Stereotypies may show some degree of variation, and may be unlike themore typical behaviors such as cribbing and licking, in that they haveno features of repetitive motion, but are characterized rather bymotionless staring or a frozen body position.

[0003] The repetitive behaviors of animals and the compulsive behaviorsof humans have both responded to treatment with some of the same drugs.See, e.g., regarding treatment of acral lick with drugs that have shownbenefit in human obsessive-compulsive disorder (OCD), Rapoport, J. L.,Clin. Neurophar., 15:Suppl. 1 Pt A:261A-262A, 1992; Rapoport, J. L. etal., Arch. Gen. Psychiatry, 49:517-521, 1992. See also Smith, K. C. andPittlekow, M. R., J. Am. Dermatol., 20:860-861, 1989, wherein it wasreported that onychophagia and skin picking responded to treatment with(−) enantiomers of opioid antagonists, which have been effective also incompulsive hair pulling in cats, feather picking in birds, acral lick indogs and cribbing in horses (Dodman, N. H., Vet. International 6:13-20,1994; Dodman, N. H. et al., J. Am. Vet. Med. Assoc. 193:815-819, 1988;Turner, R., Proceedings of Annual Conference of the Association of AvianVeterinarians: August 31-Sep. 4, 1993, Nashville, Tenn., pp. 116-118).See also U.S. Pat. No. 4,692,451, the contents of which are incorporatedherein by reference in their entirety. Studies of this type providejustification for the conclusion that the same underlying physiologicalprocesses are involved in causation of the animal and human behaviors.Therefore, they should all respond positively to new methods of therapy.

SUMMARY OF THE INVENTION

[0004] The invention relates to a method for treating a disorder inanimals, variously termed repetitive, stereotypic, or compulsivebehavior, and which can also be self-injurious, by administering to theanimal, by one or more appropriate routes and by appropriate doses, aneffective amount of one or more NMDA receptor antagonists. In somecases, the composition comprises one or more NMDA receptor antagoniststhat are not haloperidol. In some cases the composition comprises one ormore NMDA receptor antagonists, and does not comprise an opioid receptoragonist or antagonist which is primarily (−) enantiomer. In some casesthe composition comprises one or more NMDA receptor antagonists, butdoes not comprise an opioid receptor agonist or antagonist of either (+)or (−) enantiomer.

[0005] The invention, more particularly, is a method for treatingcompulsive behaviors in horses, such as crib biting, wind sucking, stallwalking, weaving, head bobbing, pawing, tonguing, self-biting, flanksucking, and head shaking, by administering to the horse a compositioncomprising one or more NMDA receptor antagonists.

[0006] In another particular embodiment, the invention is a method fortreating compulsive behaviors in dogs, such as compulsive licking (acrallick), tail chasing and whirling, pacing, fly chasing, shadow or lightchasing, excessive barking, stone eating, excessive drinking, andexcessive eating, comprising administering to the dog an effectiveamount of an NMDA receptor antagonist.

[0007] Also an embodiment of the invention is a method for treatingcompulsive behaviors in cats, such as wool sucking, compulsive licking,tail chasing, hoarding, pacing, excessive marking, compulsivemasturbation, and compulsive aggression.

[0008] A further embodiment of the invention is a method for treatingcompulsive behaviors in birds, such as feather and skin picking.

[0009] The invention relates to a method for treating a disorder (ormore than one disorder, as it is possible that two or more can occurtogether) in humans, variously termed repetitive, stereotypic, orcompulsive behavior, and which can also be self-injurious, byadministering to the human, by one or more appropriate routes and byappropriate doses, one or more NMDA receptor antagonists, therebyrelieving the frequency and/or intensity of the compulsion and reducingthe frequency and/or intensity of the behavior.

[0010] Examples of the human behaviors which can be treated by thesemethods include, but are not limited to: obsessive-compulsive disorder(with its various manifestations of checking, counting, washing toremove contamination, etc.), trichotillomania, psychogenic excoriation,nail biting, compulsive exercising, smoking compulsion, drug (opioid)addiction, and alcohol addiction. These compulsive behaviors may berelated also to compulsive gambling, compulsive shopping, and eatingdisorders.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011]FIG. 1 is a graph in which cumulative crib-bites per time afteradministration of D-methadone (diamonds), as well as the rate ofcrib-bites per 5-minute interval (squares) are plotted, showing theeffect of D-methadone on the rate of compulsive crib-biting in horses.

[0012]FIG. 2 is a bar graph in which the cumulative number of turns ofthe stall in 30 minutes are plotted for a stall-walking horse observedbefore and after the injection of dextromethorphan.Dextromethorphan-HBr, 1.0 mg/kg i.v., was injected after 60 minutes ofcontrol observations. “Saline” indicates the number of turns by thehorse, observed in 30 minutes after injection of saline. “Dextro”indicates the number of turns by the horse, observed in 30 minutes afterinjection of dextromethorphan.

[0013]FIG. 3 is a bar graph showing the time spent in three typicalbehaviors in four experiments in which the effect of dextromethorphan ona shadow-chasing dog was tested on four consecutive days. Grey indicates“searching”; black indicates “fixated”; white indicates “resting.”Dextromethorphan-HBr, 2 mg per kg p.o. was administered twice daily, andtesting was carried out one hour after the morning dose. Bars indicatethe total time of each of three behaviors during the first 10 minutesafter the beginning of testing. Time not accounted for was spent inmoving about the room, usually out of range of the camera.

[0014]FIG. 4 is a graph of the cumulative number of scratches by amouse, plotted at 10 minute intervals, when naltrexone (10 mg/kg; dots),dextromethorphan (10 mg/kg; open circles), or no compound (control; X's)is injected into the mouse 10 minutes before injection of compound40/80.

[0015]FIG. 5A is a graph of the cumulative number of scratches by amouse, plotted at 10 minute intervals, when haloperidol (2.0 mg/kg;X's), dextromethorphan (20 mg/kg; dots), or naloxone (20 mg/kg; opentriangles) is injected into the mouse 30 minutes after injection ofcompound 40/80.

[0016]FIG. 5B is a graph of the cumulative number of scratches by amouse, plotted at 10 minute intervals, when (+) methadone (5.0 mg/kg;dots), (+) methadone (10 mg/kg; open circles), or saline (X's) isinjected into the mouse 30 minutes after injection of compound 40/80.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The invention relates to methods of treating animals displayingvarious types of repetitive and/or compulsive (frequently also calledstereotypic) behaviors using compounds that are characterizable as NMDAreceptor antagonists (having specific binding activity to NMDA receptorsand/or the ability to block activation of the NMDA ligand-gated channelby an activating compound).

[0018] Compulsive or stereotypic behaviors in dogs can be put intoseveral categories. “Grooming behaviors” can include, for example, lickgranuloma (acral lick), compulsively licking objects, self-scratching,chewing feet, hair and nails, etc., flank sucking and air licking.“Locomotory behaviors” can include, for example, running and jumping,pacing, head shaking, paw shaking, tail swishing, freezing, whirling,tail chasing, walking in a pattern, as along a fence, digging and floorscratching. “Vocalization behaviors” include, for example, rhythmicbarking, growling or snarling at self, barking at food, crying andhowling. “Predatory behaviors” include, for instance, staring, airbatting, jaw snapping, pouncing, prey chasing or searching, ducking, andfly chasing. “Eating and drinking behaviors” include, for example,excessive drinking, polyphagia, excessive drooling, gravel and dirteating, stone chewing, wool sucking, and eating fabrics. “Sexualbehaviors” include, for example, compulsive mounting. See, for tablescompiling the observed behaviors of not only cats and dogs, but alsohorses, primates and other species Dodman, N. H., “Veterinary Models ofObsessive-Compulsive Disorder,” Chapter 16, pp. 319-334 InObsessive-Compulsive Disorders: Practical Management (M. A. Jenike etal., eds.), Moseby, Boston, 1998. See also N. H. Dodman et al.,“Veterinary Models of OCD,” Chapter 6, pp. 99-143, InObsessive-Compulsive Disorders: Diagnosis, Etiology and Treatment, (E.Hollander et al., eds.), Marcel Dekker, New York, 1997. See also Tables1 and 2 in Luescher, U. A. et al., “Stereotypic or Obsessive-CompulsiveDisorders in Dogs and Cats,” In Veterinary Clinics of North America:Small Animal Practice, 21(2):401-413 (March, 1991).

[0019] Cats can exhibit behaviors similar to those seen in dogs, withthe most common behaviors being those related to grooming, such asexcessive self-licking and hair chewing. Other repetitive behaviors aretail chasing, hoarding, wool sucking, pacing, excessive marking,compulsive masturbation, and compulsive aggression.

[0020] Horses have not been observed to display compulsive predatorybehaviors, but can also suffer from species-typical compulsivebehaviors, such as cribbing, wind sucking, stall walking, weaving, headbobbing, pawing, lip flapping/tonguing, head shaking, flank biting,trichotillomania, and masturbation.

[0021] Birds, especially those of the order Psittaci, which includesparakeets, cockatoos, lories, macaws, and South American and Africanparrots, are subject to compulsive behaviors, particularly featherpulling and skin picking, but also route tracing, spot picking,masturbation and regurgitation.

[0022] Compulsive behaviors exhibited by animals of the porcine speciesinclude bar biting, vacuum chewing, and chain chewing.

[0023] Animals of the ovine and bovine species can exhibit behaviorssimilar to those seen in other species. These include tonguing andcompulsive sucking, weaving, hair licking, and masturbation.

[0024] Bears in captivity have developed pacing behaviors.

[0025] Primates in captivity have been observed to have the followingcompulsive behaviors: hair pulling and skin picking (categorized as“grooming” behaviors), self sucking, licking and chewing (“consummatory”behaviors), self-directed aggression (“aggressive” behavior),masturbation and rectal probing (sexual behaviors), and bouncing inplace and somersaulting (locomotory behaviors).

[0026] Humans, as would be expected, have developed a great variety ofcompulsive behaviors, compared to those of the animals. Common humanbehaviors include: paraphilias (sexual); self-directed aggression andpyromania (aggressive); checking, avoidance of contamination (fear andavoidance); skin/nose picking, trichotillomania (grooming); gambling,hoarding (“predatory”); whirling, tics, compulsive exercising(locomotor); and binge eating (consummatory). This list, like the listsof behaviors of the animals given above, is not intended to be completeor limiting, as variations with each individual animal or human arepossible. Further descriptions of human compulsive behaviors can befound in Diagnostic and Statistical Manual of Mental Disorders(DSM-IV™), American Psychiatric Association, 1994.

[0027] Stereotypic animal behaviors have been compared toobsessive-compulsive disorder and disorders involving similar repetitiveor compulsive behaviors in humans. As Freud described compulsivebehavior, “the patient is impelled to perform actions which not onlyafford him no pleasure but from which he is powerless to desist.” It hasbeen hypothesized that a more satisfactory definition of stereotypies orcompulsive behaviors would encompass both the animal and humansyndromes, by being based on common, specific neuropathologicdifferences in the brains of animals or humans manifesting thesebehaviors, compared to animals or humans that do not manifest suchbehaviors. See discussion in Luescher, U. A. et al., “Stereotypic orObsessive-Compulsive Disorders in Dogs and Cats,” In Veterinary Clinicsof North America. Small Animal Practice, 21(2):401-413 (March 1991).

[0028] The similarities have led some to refer to not only the humanbehaviors, but also the animal behaviors, as “compulsive” behaviors or“obsessive-compulsive disorders.” See Overall, K. L., Canine Practice,17:39-42, 1992; Dodman, N. H. and B. Olivier, CNS Spectrums, 1(2):10-15,1996. It has been proposed that acral lick in dogs, and compulsive barbiting and chain chewing of tethered sows, as well as several otherbehaviors of animals, might serve as useful models of humanobsessive-compulsive disorder (Dodman, N. H. and B. Olivier, CNSSpectrums, 1(2):10-15, 1996). Compulsive self-grooming behaviors inanimals, in particular, have been compared with trichotillomania inhumans (Moon-Fanelli, A. A. et al., Chapter 3, pp. 63-92 InTrichotillomania, (D. J. Stein et al., eds.), American PsychiatricPress, Inc., Washington, D.C. The serotonin reuptake inhibitorcitalopram has been found to be useful in the treatment of OCD andpossibly compulsive hair-pulling in humans, and has been usedsuccessfully, in the majority of the dogs in the study reported, totreat acral lick dermatitis (Stein, D. J. et al., Depression andAnxiety, 8:39-42, 1998). These data provide evidence that acral lickdermatitis can be a useful animal analog of OCD.

[0029] Similarities that can be observed among the repetitive animalbehaviors, and between the repetitive behaviors of animals and therepetitive behaviors of humans, suggest a common etiology. In addition,there are studies that link one human syndrome to another. Neurologicdisorders such as epilepsy, Sydenham's chorea, and toxic and vascularlesions of the basal ganglia have been found concurrently with OCD(Freeman, J. et al., Paediatrics, 35:42-49, 1965; Kettle, P. and I.Marks, Br. J. Psychiatry, 149:315-319, 1989), leading to the suggestionthat repetitive behaviors may be a sign of acquired disease. Observationof increased rates of OCD in Tourette syndrome (TS) patients, increasedprevalence of tics and TS in OCD patients, and the increased familialrates of OCD and TS in first-degree relatives of both TS and OCDprobands lead to the conclusion that there is a genetic associationbetween the two disorders (Leonard, H. L., et al., Am. J. Psych.,149:1244-1251, 1992; Leonard, H. L., et al., Adv. Neurol., 58:83-93,1992). A study of the incidence of OCD in the first degree relatives oftrichotillomania patients found a higher lifetime prevalence of OCD inthis group than in the relatives of normal controls (Lenane, M. C. etal., J. Child Pyschol. Psychiatry, 33(5):925-933, 1992). Attentiondeficit/hyperactivity disorder occurs frequently with Tourette syndrome(see, for example, Harris, E. L. et al., J. Int. Neuropsychol. Soc.,1(6):511-516, 1995).

[0030] N-methyl-D-aspartic acid (NMDA) selectively activates a majorsubclass of glutamatergic excitatory amino acid receptors in thevertebrate central nervous system (CNS). The NMDA receptor is aligand-gated channel that is activated by the coagonists glutamate (orselectively in vitro by NMDA) and glycine acting at astrychnine-insensitive glycine site (Wong, E. H. F. and J. A. Kemp,Annu. Rev. Pharmacol. Toxicol, 31:401-425, 1991). It is further subjectto regulation by a voltage-dependent block of the channel by Mg²⁺, avoltage-independent action of Zn²⁺, the redox state of the receptor,arachidonic acid, ethanol, neurosteroids, pH and polyamines.

[0031] Although the exact structure of NMDA receptors is still a matterof debate, NMDA-sensitive ionotropic glutamate receptors probablyconsist of tetrameric, heteromeric, subunit assemblies that havedifferent physiological and pharmacological properties and aredifferentially distributed throughout the central nervous system. TheNMDA receptors are positively modulated by glycine, by polyamines(spermine and spermidine), by histamine and, under some conditions, bycations. NMDA receptors are coupled to glutamate-gated high conductancechannels permeable to K⁺, Na⁺, and Ca⁺⁺, that are critical for long-termpotentiation, and are selectively activated by the artificial glutamateanalog N-methyl-D-aspartate. There is evidence that NMDA receptors playan important role in learning and in other phenomena in the brain, suchas drug dependence and addiction, chronic pain, and CNS development, aswell as in normal or disturbed synaptic transmission in some areas ofthe CNS. See, for review on NMDA receptors, Danysz, W. and Parsons, C.G., Pharmacological Reviews, 50(4):597-664, 1998.

[0032] An NMDA receptor antagonist is any one of a number of agentswhich has been shown to bind to NMDA receptors and/or block any of thesites that bind glycine, glutamate, NMDA or phencyclidine (PCP).Blocking the NMDA receptor sites has the effect of preventing thecreation of an action potential in the cell. NMDA receptor antagonistsinclude those compounds that preferentially bind to NMDA receptors, butmay also have other activities.

[0033] NMDA receptor antagonists include the following: previouslyidentified competitive and non-competitive antagonists of NMDAreceptors, which may bind, for instance, at the glycine site (on the NR1subunit) and/or at the glutamate recognition site (on the NR2 subunit).Preferred NMDA receptor antagonists are those that have the ability tocross the blood-brain barrier and also demonstrate a low incidence ofside effects. Such NMDA receptor antagonists can include, for example,compounds known as arylcyclohexylamines such as the anesthetic ketamine,neuroleptics such as haloperidol (Coughenour, L. L. and J. J. Corden, J.Pharmacol. Exp. Ther., 280:584-592, 1997) and the anti-Parkinson drugamantadine. Ifenprodil and eliprodil are neuroprotective agents whosemechanism of action has been attributed to their NMDA antagonistproperties (Scatton, B. et al., pp. 139-154 In Direct and AllostericControl of Glutamate Receptors, Palfreyman, M. G. et al., eds., CRCPress, 1994). Trifluperidol and haloperidol have been shown to have asimilar selectivity for the NR1a/NR2B receptor subtype expressed inXenopus oocytes (Ilyin, V. et al., Soc. Neurosci. Abstracts, 21:835,1995. Memantine, felbamate, ifenprodil, eliprodil, CGS19755, remacemide,and CNS 1102 are also antagonists of NMDA receptors (Lipton, S. A. andP. A. Rosenberg, New England Journal of Medicine, 330 (9):613-622,1994). A large number of NMDA receptor antagonists have been synthesizedand tested for interaction with the NMDA receptor complex, and researchinto the synthesis and improvement of NMDA receptor antagonists iscontinuing. See, for example, U.S. Pat. No. 5,783,700, WO 97/10240, U.S.Pat. No. 5,710,168, WO 98/03189, and DE 19601782.

[0034] NMDA receptor antagonists also include newer preparations underdevelopment e.g., CP 101, 606 (Di, X. et al., Stroke. 28:2244-2251,1997) BIII CL (Grauert, M. et al., J. Pharmacol. Exp. Ther.,285:767-776, 1998); AR-RI 5896AR (Palmer, C. G. et al., J. Pharmacol.Exp. Ther., 288:121-132, 1999) LY274614 (Tiseo, P. J. and Inturrisi C.E., J. Pharmacol. Exp. Ther., 264:1090-1096, 1993); and NMDA antagoniststhat act on the glycine B site (Danysz, W. and C. G. Parsons, Pharmacol.Rev., 50:597-664, 1998).

[0035] Many different types of assays, with many variations of eachtype, have been used by those of skill in the art to test compounds forthe properties of an NMDA receptor antagonist. Triton-treated membranefractions prepared from rat telencephalon (including cortex,hippocampus, and striatum) can be used in binding assays to determineK_(D)'s of compounds; the effects of various compounds on [³H]glycinebinding can be determined, yielding a K_(i) (Kessler, M. et al., J.Neurochem, 52:1319-1328, 1989). Ebert, B. et al. (Eur. J. Pharmacol.Mol. Pharmacol., 208:49-52, 1991) have described assays that determineK_(i) values of compounds by evaluating their affinities to membranefractions isolated from various parts of the rat brain. It was foundthat the test compounds showed markedly lower affinity for the MK-801binding sites in the rat cerebellum compared to MK-801 binding sites inthe cortex (approximately 25-fold lower). K_(D) values were similar forrat cortex, hippocampus, striatum, midbrain and medulla pons, althoughB_(max) values (indicating density of binding sites) for these tissuesvaried considerably.

[0036] In other types of tests of compounds for properties of NMDAreceptor antagonists, onset and relief of block of NMDA-inducedvoltage-clamped neuron currents can be measured after application of acompound (Mealing, G. A. R. et al., J. Pharmacol. Exp. Ther.,288:204-210 (1999); Mealing, G. A. R. et al., J. Pharmacol. Exp. Ther.,281:376-383 (1997)). Trapping of block by NMDA antagonists has beenstudied by a method described also in Mealing, G. A. R. et al., J.Pharmacol. Exp. Ther., 288:204-210 (1999) and in Blanpied, T. A. et al.,J. Neurophysiol., 77:309-323 (1997), measuring current amplitudes on ratcortical neurons. Tests of the effectiveness of NMDA receptorantagonists as antinociceptive agents are the rat tail-flick test andthe formalin test, both described in Shimoyama, N. et al., J. Pharmacol.Exp. Ther., 283:648-652 (1997). Other assays for NMDA receptor bindingand effects of this binding are referred to in the review by Danysz andParsons, Pharmacological Reviews, 50(4):597-664, 1998.

[0037] Preferred NMDA receptor antagonists are those which have a K_(D)in an NMDA receptor binding assay greater than 10 μM and less than orequal to 100 μM, more preferred are those NMDA receptor antagonistswhich have a K_(D) greater than 1 μM and less than or equal to 10 μM,even more preferred are those NMDA receptor antagonists which have aK_(D) greater than 100 nM and less than or equal to 1 μM, still morepreferred are those NMDA receptor antagonists which have a K_(D) greaterthan 10 nM and less than or equal to 100 nM, and most preferred arethose NMDA receptor antagonists which have a K_(D) equal to or less than10 nM.

[0038] There is evidence for three major categories of opioid receptorsin the central nervous system. These have been designated μ, κ, and δ.Binding to the opioid receptors can be measured in assays such as thosedescribed in Kristensen, K. et al., Life Sciences, 55(2):PL45-PL50(1994), using bovine caudate nucleus. Opioid receptor binders (which acteither as an agonist or antagonist) are those compounds that bind toopioid receptors with a dissociation constant of less than about 100 nM.Preferably, opioid receptor binding molecules bind to opioid receptorswith a K_(D) of less than 10 nM. A given opioid drug may interact to avariable degree with all three types of receptors and act as an agonist,partial agonist, or antagonist, at each type of receptor. The antagonistnaloxone binds with high but variable affinity to all of thesereceptors. The term “naloxone-sensitive” is sometimes used synonymouslywith “opioid” in describing the actions of a given compound. See Jaffe,J. H. and W. R. Martin, “Opioid Analgesics and Antagonists,” pp. 485-521In The Pharmacological Basis of Therapeutics, (A. G. Gilman et al.,eds.), 8th ed., Pergamon Press, New York, 1990.

[0039] Compounds classified as opioids have the ability to bind toopioid receptors. These can be natural or synthetic compounds. It hasbeen found that some opioids tested for binding to the NMDA receptor areNMDA receptor antagonists (Ebert, B. et al, Biochemical Pharamacology.56:553-559, 1998). Within the class of compounds that are opioids andare NMDA receptor antagonists is a subset of compounds that can exist as(−) and (+) forms. Where the enantiomers have been tested for bindingaffinity to NMDA receptors, both have been found to have bindingactivity; for some of these compounds, the (+) enantiomer has beendemonstrated as having a higher affinity for NMDA receptors (Gorman, A.L., et al., Neurosci. Lett., 223:5-8, 1997; Choi, D. W. and V. Viseskul,Eur. J. Pharmacol., 155:27-35, 1988; Craviso, G. L. and Musacchio, J.M., Molec. Pharmacol. Exp. Ther., 264:1090-1096, 1993).

[0040] While Applicants do not wish to be bound by a single mechanism ofaction of the methods of the claims, one hypothesis that explains theresults observed in the Examples is that both narcotic agonists andnarcotic antagonists can bind to NMDA receptors and act as antagonistsof NMDA receptors. Support for this hypothesis can be found in thescientific literature: (1) narcotic agonists and antagonists bind toNMDA receptors (see study of inhibition of binding of[³H]dextromethorphan in Craviso, G. L. and J. M. Musacchio, Molec.Pharmacol., 23:629-640, 1983); (2) both (+) and (−) enantiomers can bindto NMDA receptors, with the (+) enantiomer in most cases having a higheraffinity for the NMDA receptor (see Craviso, G. L. and Musacchio, J. M.Molec. Pharmacol., 23:629-640, 1983); also see study of inhibition ofbinding of MK-801 to NMDA receptors in synaptic membranes from ratforebrain in Gorman, A. L. et al., Neurosci. Lett., 223:5-8, 1997); (3)like compounds previously characterized as NMDA antagonists, narcoticagonists and antagonists can protect cultured neurons from glutamatetoxicity (Choi, D. W. and Viseskul, V. Eur. J. Pharmacol., 155:27-35,1988).

[0041] Assuming that both (+) and (−) enantiomer of narcotic antagonistsdecrease stereotypic behaviors by blocking NMDA receptors, there areconsiderable advantages to be gained by employing (+) enantiomers. Theseare: (1) there is no induction of narcotic receptors; (2) narcotics canbe employed for pain relief if necessary (e.g. oral surgery or othersurgery), as (+) enantiomers of narcotic antagonists do not blocknarcotic analgesia. The (+) enantiomers, unlike some known NMDAantagonists, readily cross the blood brain barrier. They do not producetoxic side effects like dizocilpine (MK-801). There is much experiencewith dextromethrophan as an anti-tussive with very little toxicity.Furthermore, there is considerable experience in treating addiction with(−) naltrexone and with racemic methadone. Toxicity of these substancesis minimal.

[0042] Substituting (+) methadone for racemic methadone or (−) acetyl-lmethadol in the treatment of narcotic addicts would have manyadvantages, including: 1) decreased craving without maintainingaddiction; 2) no tolerance, and therefore lower doses; 3) no problemswith security or drug diversion; and 4) less difficulty in weaningaddicts. Block of NMDA receptors should also decrease craving forcocaine and alcohol (Sass, H. et al., Arch. Gen. Psychiarty, 53:673-680,1996; Mitchem, L. D. et al., Pharmacol. Biochem. Behavior, 62:97-102,1999).

[0043] Preferred compounds to be used in the treatment of repetitivebehavior disorders include (+) enantiomers of both natural and syntheticopioids, such as dextromethorphan, dextrorphan, (+) methadone and (+)pentazocine; (+) enantiomers of synthetic narcotic antagonists such as(+) naloxone, (+) naltrexone, (+) nalmefene, and (+) diprenorphine.

[0044] Compositions to be used in methods described herein for thetreatment of stereotypic, self-injurious and compulsive behaviors inanimals and in humans include those comprising NMDA receptorantagonists; those compositions comprising NMDA receptor antagonists,wherein the composition does not comprise haloperidol; thosecompositions comprising NMDA receptor antagonists, wherein thecomposition does not comprise haloperidol, and wherein the compositiondoes not comprise primarily (−) enantiomer of an opioid receptor agonistor antagonist; compositions comprising NMDA receptor antagonists,wherein the composition does not comprise haloperidol, and wherein thecomposition does not comprise an opioid receptor agonist or antagonistas (−) or (+) enantiomer; also, compositions comprising a compoundselected from the group consisting of: dextromethorphan, dextrorphan,naltrexone, naloxone, methadone, pentazocine, nalmefene, diprenorphine,nalorphine, hydromorphone, oxymorphone, hydrocodone, oxycodone,buprenorphine, butorphanol, nalbuphine, fentanyl, metazocine,cyclazocine, etazocine, and a combination of any of the preceding,wherein the compounds are predominantly (+) enantiomer.

[0045] Further compounds which can be used, preferably topically, in acomposition for the treatment of behaviors such as psychogenicexcoriation and scratching associated with pruritus are compounds suchas loperamide, MK-801, and ketamine, wherein the compound is primarily(+) enantiomer, of those that are optically active.

[0046] Animals to be treated for repetitive behaviors include, but arenot limited to, birds and mammals, for example, captive “wild” birds andmammals, such as those living in zoos or animal preserves, especiallyspecies that are predatory or can be predatory, such as feline, canineand ursine species, domestic animals, such as those raised for meat orfurs (e.g., chickens, pigs, cattle, minks), and those animals kept aspets or for recreational purposes, such as rats, mice, cats, dogs,horses, and various types of birds, such as parrots, cockatoos,parakeets, pigeons and the like.

[0047] “Horses” as used herein includes those domesticated animals thatare usually called “horses,” but also those animals that are sometimesclassified by size as being ponies or miniature horses.

[0048] “Of an equine species” refers herein not only to horses, donkeys,and the like but also to equine hybrids, such as mules and hinnies.

[0049] Similarly, “of a canine species” refers herein not only todomestic dogs, but also to wild dogs and canine hybrids.

[0050] Stereotypic movement disorder of humans is characterized by“repetitive, seemingly driven, and nonfunctional motor behavior (e.g.,hand shaking or weaving, body rocking, head banging, mouthing ofobjects, self-biting, picking at skin or bodily orifices, hitting ownbody).” The severity of the behavior is such that it interferes withnormal activities or results in bodily injury if preventive measureswere not used. Self-injurious behaviors occur in certain medicalconditions associated with mental retardation (e.g., fragile X syndrome,de Lange syndrome, and Lesch-Nyhan syndrome, characterized byself-biting). See pages 118-121 In Diagnostic and Statistical Manual ofMental Disorders (DSM-IV™), American Psychiatric Association, 1994.

[0051] Smoking compulsion in humans is the urge to perform the act ofsmoking (tobacco cigarettes, cigars, or tobacco contained in anothervessel or vehicle). The act of smoking is the physical manipulation ofthe cigarette or other tobacco vehicle and the conscious control ofbreathing that is normally performed in the course of taking in andblowing out the tobacco smoke, primarily involving the hands and mouth,in a kind of ritual. Smoking compulsion usually accompanies thewell-documented nicotine addiction resulting from frequent and habitualtobacco smoking, but can be thought of as a compulsion which is separatefrom the craving satisfied by the administration of nicotine by a routeother than smoking. This compulsion to smoke may be responsible for thefailure of the simple administration of decreasing doses of nicotine (bytransdermal patch or by nicotine-containing chewing gum, for example) towean smokers from their smoking habit.

[0052] Psychogenic excoriation (also sometimes referred to as neuroticexcoriation or pathologic skin picking) is a human disordercharacterized by excessive scratching, picking, gouging, or squeezingthe skin, and occurs in approximately 2% of dermatology clinic patients,mostly female (Gupta, M. A. et al., Compr. Psychiatry, 27:381-386,1986). It has been hypothesized that psychogenic excoriation is animpulse control disorder which is related to obsessive-compulsivedisorder, or which is a manifestation of obsessive-compulsive disorder(McElroy, S. L. et al., J. Clin. Psychiatry, 55:33-53, 1994). Patientswith psychogenic excoriation have responded to serotonin reuptakeinhibitors such as fluoxetine and sertraline (Gupta, M. A. and A. K.Gupta, Cutis, 51:386-387, 1993; Stein, D. J. et al., Psychosomatics,34:177-181, 1993; Phillips, K. A. and S. L. Taub, Psychopharmacol.Bull., 31:279-288, 1993; Kalivas, J. et al., Arch. Dermatol.,132:589-590, 1996). In a study of fluvoxamine (a selective serotoninreuptake inhibitor used in the treatment of OCD) for the treatment ofpsychogenic excoriation, patients showed significant improvement(Arnold, L. M. et al., Journal of Clinical Psychopharmacology, 19:15-18,1999).

[0053] In what can also be considered a related self-injurious behavior,scratching associated with pruritis has been shown to respond toperipherally acting opiates, such as loperamide (U.S. Pat. No.5,849,761; U.S. Pat. No. 5,849,762). An animal model, using injectionsof a chemical irritant, can be used to test the effectiveness of agentsto treat scratching associated with pruritis (Kuraishi, Y. et al.,European Journal of Pharmacology, 275: 229-233, 1995).

[0054] An effective amount of an agent, a compound or a drug is anamount that produces a measurable improvement in the condition to betreated (e.g., a reduction in the frequency of the behavior exhibited inthe human or animal, compared to the frequency of behaviors exhibited ina human or animal left untreated or sham-treated).

[0055] A compound primarily in the (+) form can be from greater than 50%to 100% (+) enantiomer. Similarly, a compound that is primarily (−) canbe from greater than 50% (in a racemic mixture) to 100% (−) enantiomer.Compositions comprising primarily the (+) form of an opioid can havegreater than 50% to 60% (+) enantiomer, but preferably have greater than60% to 70% (+) enantiomer, more preferably greater than 70% to 80% (+)enantiomer, still more preferably greater than 80% to 90% (+)enantiomer, and most preferably, more than 90% (+) enantiomer.

[0056] Agents to be used in methods of treating a human or an animal fora repetitive and/or compulsive behavior disorder can be employed incombination with a non-sterile or sterile carrier or carriers for usewith cells, tissues or organisms, such as a pharmaceutical carriersuitable for administration to a human or animal subject. Suchcompositions comprise, for instance, a media additive or atherapeutically effective amount of an agent and a pharmaceuticallyacceptable carrier or excipient. Such carriers may include, but are notlimited to, saline, buffered saline, dextrose, water, ethanol,surfactants, such as glycerol, excipients such as lactose andcombinations thereof The formulation can be chosen by one of ordinaryskill in the art to suit the mode of administration. The chosen route ofadministration will be influenced by such factors as the solubility,stability and half-life of the agent, for instance.

[0057] Agents to be used in the treatment of a repetitive and/orcompulsive behavior disorder may be employed alone or in conjunctionwith other compounds, such as other therapeutic compounds. Thepharmaceutical compositions may be administered in any effective,convenient manner, including administration by topical, oral, anal,vaginal, intravenous, intraperitoneal, intramuscular, subcutaneous,intranasal, transdermal or intradermal routes, among others. In therapyor as a prophylactic, the active agent may be administered to a subjectas an injectable composition, for example as a sterile aqueousdispersion, preferably isotonic, or “packaged” as liposomes ormicrospheres.

[0058] When injectable compositions are desired, the functionalantagonists of the present invention may be formulated, for example,into preparations for injection by dissolving, suspending or emulsifyingthem in an aqueous or non-aqueous solvent, such as vegetable oil,synthetic aliphatic acid glycerides, esters of higher aliphatic acids orpropylene glycol; and if desired, with conventional additives such assolubilizers, isotonic agents, suspending agents, emulsifying agents,stabilizers and preservatives.

[0059] Alternatively, if one wishes to prepare an oral dosage formcontaining one of the functional antagonists herein encompassed,commonly used and pharmaceutically acceptable tableting excipients, suchas lactose, microcrystalline cellulose, corn starch, stearic acid, orthe like, may be used, if desired, to prepare such dosage forms.

[0060] Alternatively, the composition may be formulated for topicalapplication, for example, in the form of ointments, creams, lotions, eyeointments, eye drops, ear drops, mouthwash, impregnated dressings andsutures and aerosols, and may contain appropriate conventionaladditives, including, for example, preservatives, solvents to assistdrug penetration, and emollients in ointments and creams. Such topicalformulations may also contain compatible conventional carriers, forexample cream or ointment bases, and ethanol or oleyl alcohol forlotions.

[0061] In addition, the amount of the compound will vary depending onthe size, age, body weight, general health, sex, and diet of the host,and the time of administration, the biological half-life of thecompound, and the particular characteristics and symptoms of thedisorder to be treated. Adjustment and manipulation of established doseranges are well within the ability of those of skill in the art, andpreferably minimize side effects and toxicity.

EXEMPLIFICATION Example 1 Treatment of Cribbing in Horses

[0062] Horses were admitted to the Large Animal Hospital of TuftsUniversity School of Veterinary Medicine or were tested in their homebarn. Cribbing straps and food were removed prior to testing. Controlrates of crib-biting were observed and recorded for 5 minute intervalsfor one hour or more after an intravenous injection of 0.15 M saline.Test drugs were administered orally (by gavage) or by injection into thejugular vein. Solutions were made up with physiological saline andsterilized by filtration through a 0.2 micron filter (Millipore).

[0063] For the experimental data shown in FIG. 1, after establishment ofa stable control rate of approximately 10 crib-bites per minute, 50 mgof D-methadone-HCl in 25 ml saline was injected i.v. In FIG. 1, thecumulative number of crib-bites was plotted against time as was the rateper 5 minute interval (Shuster, L. and N. H. Dodman, pp. 185-202, InPsychopharmacology of Animal Behavior Disorders, (N. H. Dodman and L.Shuster, eds.), Blackwell Scientific, Malden, Mass., 1998). The ratedecreased between the second and the fifth 5-minute interval followinginjection. The control rate then resumed during the next 80 minutes ofobservation. Horses were observed continuously during scoring for sideeffects that might be attributed to the treatment. These includedchanges in posture, disposition and motor activity. See also Table 1.

Example 2 Treatment of Stall-Walking in Horses

[0064] Dextromethorphan-HBr, 1.0 mg/kg i.v., was injected after 60minutes of control observations, to test its effect on a stall-walkinghorse. When measuring “stall walking” locomotor activity, each circuitaround the stall was scored as one rotation. Cumulative rotations per 5minute interval were plotted against time to establish the rate ofcircling. The results of the experiment are plotted in FIG. 2. See alsoTable 1. TABLE 1 Effect of some Drug Treatments on the Rate of CribBiting Crib-biting Frequency Number number per per minute minuteDuration Before After Horse Drug Dose & Route of Effect treatmenttreatment CB (−) naloxone 65 min. 12 0.1 .04 mg/kg, i.v. (10 min lag) CB(+) naloxone 60 min. 10 6.6 0.12 mg/kg, i.v. (30 min lag) CB (+)naloxone 60 min. 9.2 0.8 0.18 mg/kg, i.v. (no lag) CB Dextromethorphan90 min. 8 1.7 1.0 mg/kg, p.o. (35 min lag) CB Dextromethorphan 35 min7.6 0.3 1.0 mg/kg, i.v. (no lag) CB (+) Methadone 20 min 8.8 2.6 0.2mg/kg, i.v. (10 min lag) CB (+) Methadone 10 min 8.2 5.5 .01 mg/kg, i.v.CB ketamine 50 min 8.2 1.3 0.2 mg/kg, i.v. (no lag) FritoDextromethorphan 100 min 3.5 1.8 3.2 mg/kg p.o. (30 min lag) Full CircleDextromethorphan 45 min 3.5 turns .3 turns (turning) 1.0 mg/kg, i.v. (nolag) per min. per min.

Example 3 Treatment of Light/Shadow-Chasing in Dogs

[0065] Behavior of a shadow-chasing dog was filmed with a video camerafor 10 minutes after the onset of testing in the owner's home. Tostimulate the dog, the owner moved around a flashlight beam on the floorfor 5 seconds. The typical response after the light was turned off wasfrantic searching for the light followed by fixed staring at the floor.Dextromethorphan-HBr, 2 mg per kg p.o. was administered twice daily andtesting was carried out one hour after the morning dose. Results areshown in FIG. 3.

Example 4 Mouse Model for Pruritus

[0066] The animals used were BALB/c male mice, weighing 27-33 g. Onemouse was used per compound tested, except for two control micereceiving saline; two different mice were tested with (+) methadone,each with a different dose. Compound 48/80 (Kuraishi, Y. et al.,European Journal of Pharmacology, 275:229-233, 1995), 0.5 mg/ml insaline, was injected subcutaneously in a volume of 0.1 ml, between theshoulder blades of the mouse. Test compounds, dissolved in saline, wereinjected intraperitoneally in a volume of 0.1 ml per 10 g, either 10minutes before or 30 minutes after injection of compound 48/80. Thecumulative number of scratches with a hind leg were recorded at 10minute intervals for 60 minutes following the injection of compound48/80. See Tables 2 and 3, as well as FIGS. 4, 5A and 5B, showing theeffectiveness of the compounds tested: naltrexone, dextromethorphan, (+)methadone, haloperidol, and (+) naloxone. TABLE 2 Effect of NMDABlockers on Pruritus in Mouse: Blocker Administered 10 Minutes Before48/80 Time Cumulative Scratches Naltrexone Dextromethorphan MinutesControl 10 mg/kg 10 mg/kg 10 5 0  1 20 52 0  57 30 166 0 105 40 277 1157 50 364 61 182 60 498 73 192 Time (+) methadone 10 mg/kg Control 10 0 3 20 0  79 30 0  99 40 0 227 50 0 404 60 0 456

[0067] TABLE 3 Effect of NMDA Blockers on Pruritus in Mouse: CompoundAdministered 30 Minutes After 48/80 Cumulative Scratches (+) (+) (+)Methadone Methadone Naloxone Dextromethorphan Haloperidol Time Saline 5mg/kg 10 mg/kg 20 mg/kg 20 mg/kg 2.0 mg/kg 10 4 0 6 4 47 2 20 70 56 3848 125 87 30 134 114 106 105 158 108 40 181 145 107 112 171 137 50 220210 107 146 178 137 60 297 267 107 175 185 142

[0068] All references cited herein not previously specifically stated asbeing incorporated by reference are hereby incorporated by reference intheir entirety.

[0069] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the spirit and scope of theinvention as defined by the appended claims.

What is claimed is:
 1. A method for treating the obsessive-compulsivecomponents of Tourette syndrome in a human, comprising administering tothe human an effective amount of a composition comprising one or moreNMDA receptor antagonists, wherein the composition does not comprisehaloperidol and does not comprise (−) naloxone.
 2. A method for treatingthe obsessive-compulsive components of Tourette syndrome in a human,comprising administering to the human an effective amount of acomposition comprising one or more NMDA receptor antagonists, whereinthe composition does not comprise haloperidol and does not compriseprimarily (−) enantiomer of an opioid receptor agonist or antagonist. 3.A method of claim 1, wherein the composition comprises one or morecompounds selected from the group consisting of: dextromethorphan,dextrorphan, naltrexone, naloxone, methadone, pentazocine, nalmefene,diprenorphine, nalorphine, hydromorphone, oxymorphone, hydrocodone,oxycodone, buprenorphine, butorphanol, nalbuphine, fentanyl, metazocine,cyclazocine, etazocine, and a combination of any of the preceding,wherein the compounds are predominantly (+) enantiomer.
 4. A method fortreating the obsessive-compulsive components of trichotillomania in ahuman, comprising administering to the human an effective amount of acomposition comprising one or more NMDA receptor antagonists, whereinthe composition does not comprise haloperidol.
 5. A method of claim 4,wherein the composition comprises a compound selected from the groupconsisting of: dextromethorphan, dextrorphan, naltrexone, naloxone,methadone, pentazocine, nalmefene, diprenorphine, nalorphine,hydromorphone, oxymorphone, hydrocodone, oxycodone, buprenorphine,butorphanol, nalbuphine, fentanyl, metazocine, cyclazocine, etazocine,and a combination of any of the preceding, wherein the compounds arepredominantly (+) enantiomer.
 6. A method for treating theobsessive-compulsive components of stereotypic movement disorder in ahuman, comprising administering to the human an effective amount of acomposition comprising one or more NMDA receptor antagonists.
 7. Thecomposition of claim 6, wherein the composition does not comprisehaloperidol.
 8. The method of claim 7, wherein the composition does notcomprise primarily (−) enantiomer of an opioid receptor agonist orantagonist.
 9. The method of claim 6, wherein the composition comprisesa compound selected from the group consisting of: dextromethorphan,dextrorphan, naltrexone, naloxone, methadone, pentazocine, nalmefene,diprenorphine, nalorphine, hydromorphone, oxymorphone, hydrocodone,oxycodone, buprenorphine, butorphanol, nalbuphine, fentanyl, metazocine,cyclazocine, etazocine, and a combination of any of the preceding,wherein the compounds are predominantly (+) enantiomer.
 10. A method fortreating the obsessive-compulsive components of smoking in a human,comprising administering to the human an effective amount of acomposition comprising one or more NMDA receptor antagonists.
 11. Themethod of claim 10, wherein the NMDA receptor antagonist is not anopioid receptor agonist or antagonist.
 12. The method of claim 10,wherein the composition comprises a compound selected from the groupconsisting of: dextromethorphan, dextrorphan, naltrexone, naloxone,methadone, pentazocine, nalmefene, diprenorphine, nalorphine,hydromorphone, oxymorphone, hydrocodone, oxycodone, buprenorphine,butorphanol, nalbuphine, fentanyl, metazocine, cyclazocine, etazocine,and a combination of any of the preceding, wherein the compounds arepredominantly (+) enantiomer.
 13. A method for treating theobsessive-compulsive components of excoriation in a human, comprisingadministering to the human an effective amount of a compositioncomprising one or more NMDA receptor antagonists, wherein thecomposition does not comprise (−) naltrexone.
 14. The method of claim13, wherein the composition comprises a compound selected from the groupconsisting of: dextromethorphan, dextrorphan, naltrexone, naloxone,methadone, pentazocine, nalmefene, diprenorphine, nalorphine,hydromorphone, oxymorphone, hydrocodone, oxycodone, buprenorphine,butorphanol, nalbuphine, fentanyl, metazocine, cyclazocine, etazocine,and a combination of any of the preceding, wherein the compounds arepredominantly (+) enantiomer.
 15. A method for treating theobsessive-compulsive components of alcoholism in a human, comprisingadministering to the human an effective amount of a compositioncomprising one or more compounds selected from the group consisting of:dextromethorphan, dextrorphan, naltrexone, naloxone, methadone,pentazocine, nalmefene, diprenorphine, nalorphine, hydromorphone,oxymorphone, hydrocodone, oxycodone, buprenorphine, butorphanol,nalbuphine, fentanyl, metazocine, cyclazocine, etazocine, and acombination of any of the preceding, wherein the compounds arepredominantly (+) enantiomer.
 16. A method for treating theobsessive-compulsive components of opioid addiction in a human,comprising administering to the human an effective amount of acomposition comprising one or more compounds selected from the groupconsisting of: dextromethorphan, dextrorphan, naltrexone, naloxone,methadone, pentazocine, nalmefene, diprenorphine, nalorphine,hydromorphone, oxymorphone, hydrocodone, oxycodone, buprenorphine,butorphanol, nalbuphine, fentanyl, metazocine, cyclazocine, etazocine,and a combination of any of the preceding, wherein the compounds arepredominantly (+) enantiomer.
 17. A method for treating theobsessive-compulsive components of scratching in a human, comprisingadministering to the human an effective amount of a compositioncomprising one or more NMDA receptor antagonists.
 18. A method of claim17, wherein the composition does not comprise (−) naloxone.
 19. Themethod of claim 17, wherein the composition comprises a compoundselected from the group consisting of: dextromethorphan, dextrorphan,naltrexone, naloxone, methadone, pentazocine, nalmefene, diprenorphine,nalorphine, hydromorphone, oxymorphone, hydrocodone, oxycodone,buprenorphine, butorphanol, nalbuphine, fentanyl, metazocine,cyclazocine, etazocine, and a combination of any of the preceding,wherein the compounds are predominantly (+) enantiomer.
 20. The methodof claim 1, wherein the NMDA receptor antagonist is (+) methadone. 21.The method of claim 3, wherein the methadone is (+) methadone.
 22. Themethod of claim 4, wherein the NMDA receptor antagonist is (+)methadone.
 23. The method of claim 10, wherein the NMDA receptorantagonist is (+) methadone.
 24. The method of claim 12, wherein themethadone is (+) methadone.
 25. The method of claim 13, wherein the NMDAreceptor is (+) methadone.
 26. The method of claim 14, wherein themethadone is (+) methadone.
 27. The method of claim 17, wherein the NMDAreceptor is (+) methadone.
 28. The method of claim 19, wherein themethadone is (+) methadone.
 29. A method for treating theobsessive-compulsive components of pruritis in a human, comprisingadministering to the human an effective amount of a compositioncomprising one or more NMDA receptor antagonists.
 30. The method ofclaim 29, wherein the composition does not comprise (−) naloxone. 31.The method of claim 29, wherein the composition comprises a compoundselected from a group consisting of: dextromethorphan, dextrorphan,naltrexone, naloxone, methadone, pentazocine, nalmefene, diprenorphine,nalorphine, hydromorphone, nalbuphine, fentanyl, metazocine,cyclazocine, etazocine, and a combination of any of the preceding,wherein the compounds are predominantly (+) enantiomer.
 32. The methodof claim 29, wherein the NMDA receptor antagonist is methadone.
 33. Themethod of claim 31, wherein the methadone is (+) methadone.